US Patent 8,110,225: Dantrolene Sodium Formulation Scope, Expiration, and Patent Landscape

US Patent No. 8,110,225 protects a low-volume, rapidly reconstitutable injectable dantrolene sodium formulation. Its core requirements are micronized dantrolene sodium particles, a water-soluble polysorbate, and sorbitol or mannitol. The formulation must reconstitute into a colloidal dispersion suitable for intravenous injection at materially higher concentrations than legacy dantrolene products.

The patent is directed to formulation composition and reconstitution methods, not to dantrolene sodium as an active pharmaceutical ingredient. Its commercial relevance is tied principally to Ryanodex, Eagle Pharmaceuticals' 250-mg dantrolene sodium product.

What does US Patent 8,110,225 protect?

The patent covers a dry formulation that becomes an injectable colloidal dispersion after adding water. Independent claim 1 establishes the principal composition scope:

Required element	Claim requirement
Active ingredient	Dantrolene sodium
Particle size	Average particle diameter below about 2 microns
Surfactant	Water-soluble polysorbate
Bulking or stabilizing agent	Sorbitol or mannitol
Reconstituted form	Colloidal dispersion
Injectable concentration	3.33 mg/mL to 167 mg/mL
Intended use	Safe intravenous administration and ready for injection

The claim uses "consisting essentially of" language. That wording generally permits additional ingredients that do not materially alter the basic and novel characteristics of the formulation. It is narrower than an open "comprising" claim for the listed core components, but it is not necessarily limited to only the named ingredients.

The claimed invention addresses the poor aqueous solubility and large reconstitution volume associated with conventional dantrolene sodium products. The formulation uses small particles and excipients to produce a concentrated injectable dispersion without relying on a conventional fully dissolved solution.

How do the 20 claims divide between formulation and method protection?

Claims 1 through 9 cover dry formulations. Claims 10 through 20 cover reconstitution methods.

Composition claims

Claims 1 and 2 recite substantially the same formulation architecture. Claim 2 is a narrower "consisting essentially of" version of claim 1.

Claims 3 and 4 narrow the reconstituted concentration:

30 mg/mL to 80 mg/mL;
10 mg/mL to 60 mg/mL; or
50 mg/mL specifically.

Because the ranges overlap, a product at 50 mg/mL falls within the concentration limitations of both claims 3 and 4.

Claim 5 adds a particle distribution limitation requiring at least 95% of dantrolene sodium particles to be no more than 0.8 microns in diameter. This is materially narrower than the average-particle-size requirement in claim 1 and creates a potential evidentiary issue over particle-size testing methodology.

Claim 6 requires mannitol and caps the amount at no more than 30 mg of mannitol per milligram of dantrolene. The ratio is broad. At the commercial 50-mg/mL concentration, the relevant commercial formulation would likely fall well below this ceiling.

Claim 7 narrows the polysorbate to one having solubility of at least 5 mg/mL. Claims 8 and 9 add PVP, or polyvinylpyrrolidone.

Method claims

Claim 10 covers combining the dry formulation with water to produce the injectable dispersion. At least one of the following process conditions must be present:

A single person performs the step;
The formulation is reconstituted by hand shaking;
Reconstitution occurs in a single vial or syringe; or
Reconstitution takes one minute or less.

The claim also requires a dantrolene concentration of 3.33 mg/mL to 166.67 mg/mL.

Claims 11 and 12 narrow the method to the same concentration ranges appearing in claims 3 and 4. Claims 13 through 15 narrow the formulation composition and add PVP.

Claim 16 covers a method using 3 mL to 150 mL of water to produce a liquid formulation containing approximately 500 mg of dantrolene sodium. Claims 17 through 20 add hand shaking, vortexing, reconstitution within one minute, and PVP.

What are the most important claim limitations for infringement analysis?

A potentially infringing product must satisfy the limitations cumulatively. The principal limitations are:

Dry, rather than already-liquid, dosage form;
Dantrolene sodium particle size below about 2 microns on average;
Water-soluble polysorbate;
Sorbitol or mannitol;
Reconstitution into a colloidal dispersion;
Injectable concentration within the claimed range;
Intravenous safety and readiness for injection;
For method claims, the specified water volume, concentration, and reconstitution procedure.

A formulation containing dantrolene sodium, polysorbate, and mannitol would not necessarily infringe solely because it is concentrated. Particle size and the character of the reconstituted product are central limitations.

A formulation that uses a different surfactant, such as a non-polysorbate surfactant, may avoid literal infringement if the substitute is not a water-soluble polysorbate. A formulation using neither sorbitol nor mannitol would present a similar literal-infringement defense. The doctrine of equivalents could still be relevant, but the specific excipient selections and particle-size limitations may create prosecution-history and vitiation constraints.

How should “colloidal dispersion” and “safe for intravenous administration” be interpreted?

The claims do not require the dantrolene sodium to be molecularly dissolved. They require a colloidal dispersion of submicron or micron-scale particles after reconstitution.

This distinction is commercially important. A competitor may attempt to design around the patent by producing:

A true molecular solution;
A dispersion with particles above the claimed size;
A formulation using a different stabilizer system;
A formulation that requires materially longer or more complex reconstitution.

The phrases "safe for intravenous administration" and "ready for injection" are functional limitations. They connect the formulation to clinical and product-performance characteristics rather than merely to ingredient identity. In litigation, evidence could include particulate matter, injectability, toxicity, osmolality, stability, reconstitution time, and compatibility with intravenous administration.

"Safe" does not eliminate the need to establish the structural and concentration limitations. A product cannot be brought within the claim merely by showing that it is clinically injectable if it lacks the required particle-size, polysorbate, or sorbitol/mannitol elements.

What formulation does Ryanodex use compared with legacy dantrolene products?

Ryanodex is the commercial product most closely associated with the claimed technology. The FDA-approved product is supplied as a 250-mg vial and is reconstituted with 5 mL of sterile water, producing a nominal concentration of 50 mg/mL.[2]

Attribute	Ryanodex	Conventional dantrolene sodium injection
Dantrolene per vial	250 mg	Commonly 20 mg
Reconstitution volume	5 mL	Approximately 60 mL for many legacy products
Nominal concentration	50 mg/mL	Approximately 0.33 mg/mL
Claimed concentration range	Within claims 3, 4, 10, 11 and 12	Generally outside the high-concentration ranges
Product type	Dry formulation for rapid reconstitution	Dry formulation requiring substantially larger volume

The claims are therefore aligned with the product's principal commercial distinction: rapid preparation of concentrated dantrolene sodium for malignant hyperthermia treatment.

When does US Patent 8,110,225 lose exclusivity?

The patent's nominal term is expected to run through approximately August 2026, based on the patent family's 2006 priority and the applicable 20-year patent-term framework.[1] The precise expiration date should be taken from the current USPTO patent record and any applicable patent-term adjustment or disclaimer data.

Patent expiration does not automatically eliminate all market barriers. A commercial entrant must also consider:

Other unexpired patents in the Ryanodex patent family;
FDA marketing exclusivity;
Orange Book listings;
Product-specific regulatory requirements;
Manufacturing know-how and particle-size control;
Litigation settlements or launch licenses.

Dantrolene sodium is an old active ingredient. Ryanodex therefore did not receive new chemical entity exclusivity based on the active ingredient. Its regulatory protection was more likely tied to the NDA, clinical-investigation exclusivity, and listed patents.

What is the Orange Book and FDA status of Ryanodex?

Ryanodex was approved by the FDA in July 2014 under NDA 206620 for the treatment of malignant hyperthermia.[2] The product is a dantrolene sodium injection supplied as a 250-mg vial.

The Orange Book is the principal source for determining whether US Patent 8,110,225 is currently listed against the approved Ryanodex product and whether later patents remain listed.[3] Patent listing status can change through FDA submissions, delisting, expiration, or product-specific regulatory actions.

For generic applicants, the relevant pathway would generally be an ANDA supported by a Paragraph IV certification if the applicant seeks approval before expiration of a listed patent. A Paragraph IV certification alleges that the listed patent is invalid, unenforceable, or not infringed.

Which companies are likely to challenge the Ryanodex patent estate?

The principal potential challengers are generic injectable manufacturers with capabilities in:

Sterile powder filling;
Micronization or particle-size control;
Surfactant-containing injectable formulations;
Rapid reconstitution products;
FDA ANDA development.

The competitive group typically includes established generic injectable companies such as Hikma, Fresenius Kabi, Sandoz, Teva, Pfizer's Hospira business, Eugia, Amneal, and Par Pharmaceutical. A company's presence in injectable dantrolene does not establish that it has filed a Paragraph IV challenge.

Public confirmation of a challenge requires an FDA Paragraph IV notice, Abbreviated New Drug Application litigation, a district-court complaint under 35 U.S.C. §271(e)(2), or a disclosed settlement. Patent ownership, ANDA filing, and commercial launch status should not be inferred from generic manufacturing capability alone.

What patent litigation and settlement risks affect generic entry?

A Paragraph IV notice concerning an Orange Book-listed Ryanodex patent can trigger a 45-day period for the NDA holder to bring an infringement action. A timely suit generally creates a 30-month stay of ANDA approval, subject to statutory exceptions and court decisions.[4]

For US Patent 8,110,225, litigation would likely focus on:

Whether the accused product has an average particle size below 2 microns;
Whether at least 95% of particles are no more than 0.8 microns;
Whether the surfactant qualifies as a water-soluble polysorbate;
Whether sorbitol or mannitol is present;
Whether reconstitution produces a colloidal dispersion;
Whether the product is ready for injection within the claimed process conditions.

Validity attacks could address written description, enablement, anticipation, obviousness, indefiniteness, and claim construction. The strongest prior-art search areas are earlier dantrolene injectable formulations, nanosuspensions, particle-size reduction, polysorbate-stabilized injectable dispersions, and high-concentration parenteral products.

Settlement agreements could provide an authorized launch date before patent expiration. Such agreements may include licenses, supply arrangements, delayed-entry dates, or restrictions on formulation and manufacturing approaches. No settlement date should be assumed without a public agreement, court filing, or FTC disclosure.

How strong is the patent estate for a generic challenge?

US Patent 8,110,225 has meaningful commercial coverage because its limitations track the product's practical performance characteristics. The particle-size and excipient requirements provide structural anchors, while colloidal-dispersion and rapid-reconstitution language ties the claims to product behavior.

Strength factor	Assessment
Commercial relevance	High for concentrated, rapidly reconstituted dantrolene
Claim breadth	Moderate; multiple mandatory formulation elements limit reach
Design-around potential	Meaningful through surfactant, excipient, particle-size, or solution changes
Evidence burden	High for particle-size distribution and colloidal state
Method-claim exposure	Narrower because specific reconstitution acts are required
Small-molecule biosimilar risk	Not applicable
Manufacturing barrier	Moderate to high for sterile submicron-particle products
Expiration sensitivity	High because the principal term is near the end of its life

The composition claims are likely more important than the method claims. A manufacturer can avoid some method claims by changing reconstitution instructions or procedure, but it may still face composition claims if the marketed vial contains the claimed formulation.

What manufacturing and intellectual-property barriers remain after patent expiration?

Patent expiration removes the exclusionary right under the patent, but it does not eliminate technical barriers. A competing manufacturer would need to reproduce or replace several performance characteristics:

Consistent submicron dantrolene particle size;
Physical stability during dry storage;
Rapid wetting and dispersion;
Low particulate burden;
Acceptable sterility and endotoxin profile;
Reliable 50-mg/mL reconstitution;
Container-closure compatibility;
Commercial-scale sterile manufacturing.

Trade secrets may protect milling parameters, excipient ratios, drying conditions, vial filling, and analytical methods. Those protections do not block independent development, but they can increase development time and batch-failure risk.

How does US Patent 8,110,225 compare with method-of-use and formulation patents?

US 8,110,225 is principally a formulation and reconstitution patent.

Protection category	Coverage under US 8,110,225
Active ingredient composition	No broad protection for dantrolene sodium itself
Injectable formulation	Yes
Particle-size architecture	Yes
Surfactant and excipient system	Yes
Concentration	Yes
Reconstitution method	Yes
Malignant hyperthermia treatment method	Not the principal claim focus
Manufacturing process	Limited; claims focus on combining dry formulation with water
Biosimilar protection	No, because dantrolene sodium is a small molecule

A complete freedom-to-operate review should separate this patent from later continuation patents, Orange Book listings, method-of-use rights, and any patents covering specific excipient ratios, drying processes, container systems, or commercial presentation.

Key Takeaways

US 8,110,225 protects a dry, concentrated dantrolene sodium formulation for rapid intravenous reconstitution.
The core combination is sub-2-micron dantrolene sodium, a water-soluble polysorbate, and sorbitol or mannitol.
The 50-mg/mL concentration associated with Ryanodex is expressly covered by dependent claims.
Claims 10 through 20 add reconstitution procedures, including hand shaking, single-vial preparation, rapid preparation, and specified water volumes.
Ryanodex was FDA-approved in July 2014 under NDA 206620.
The patent's nominal expiration is approximately August 2026, subject to the official patent-term record and any applicable adjustment.
Generic risk depends on the full patent estate, not on US 8,110,225 alone.
The principal design-around options are changing particle size, replacing polysorbate, replacing sorbitol or mannitol, producing a true solution, or altering the reconstitution process.
Dantrolene sodium does not present a biosimilar issue because it is a small-molecule drug.
The strongest litigation evidence would concern particle-size distribution, excipient identity, colloidal dispersion, and reconstitution performance.

FAQs About US Patent 8,110,225

Is Ryanodex covered by US Patent 8,110,225?

US 8,110,225 is directed to the formulation characteristics associated with concentrated, rapidly reconstitutable dantrolene sodium products such as Ryanodex. Current Orange Book listing status must be confirmed against the FDA's active listing.

Does a 50-mg/mL dantrolene product infringe automatically?

No. Concentration alone is insufficient. The product must also satisfy the particle-size, polysorbate, sorbitol-or-mannitol, dispersion, and other applicable claim limitations.

Can a generic avoid the patent by using a different surfactant?

Potentially, if the substitute is not a water-soluble polysorbate and the product does not satisfy the claims under an equivalents analysis. The full formulation and prosecution history remain material.

Are conventional Dantrium dantrolene vials covered by these claims?

A conventional low-concentration dantrolene product may fall outside the high-concentration dependent claims. It could still require analysis under the broader concentration ranges and formulation limitations in the independent claims.

Does patent expiration permit immediate generic launch?

No. Launch timing also depends on other unexpired patents, FDA approval, Orange Book listings, litigation stays, settlement terms, manufacturing readiness, and regulatory exclusivity.

References

United States Patent and Trademark Office. (2012). United States Patent No. 8,110,225: Dantrolene formulations. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2014). Ryanodex prescribing information, NDA 206620.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Code, 21 U.S.C. § 355(j), Abbreviated applications and patent certifications.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2004262507	⤷ Start Trial
Canada	2516667	⤷ Start Trial
European Patent Office	1435781	⤷ Start Trial
European Patent Office	1603513	⤷ Start Trial
Japan	2007525439	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,110,225

Summary for Patent: 8,110,225